Inverse relationship between leukaemic cell burden and plasma concentrations of daunorubicin in patients with acute myeloid leukaemia

Abstract

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT• In vitro studies show that daunorubicin (DNR) cytotoxicity decreases with increasing cell density because of a high cellular uptake and depletion of drug in the medium.• It is not known whether such an effect also occurs in vivo. WHAT THIS STUDY ADDS• We have shown that a large leukaemic cell burden lowers the plasma concentration of DNR in patients with acute myeloid leukaemia.• Our analysis supports that a large leukaemic cell burden increases the central volume of distribution for DNR.• Our study indicates that a dose adjustment of DNR may be of importance in acute myeloid leukaemia patients with high white blood cell counts. AIMSIt has been shown that the cellular uptake and cytotoxicity of anthracyclines decrease with increasing cell density in vitro, an event termed 'the inocculum effect' . It is not known whether such an effect occurs in vivo. In this study the relationships between white blood cell (WBC) count, plasma and cellular concentrations of daunorubicin (DNR) in patients with acute myeloid leukaemia were investigated. METHODSPlasma and mononuclear blood cells were isolated from peripheral blood from 40 patients with acute myeloid leukaemia at end of infusion (time 1 h), 5 and 24 h following the first DNR infusion. DNR concentrations were determined by high-pressure liquid chromatography and related to the WBC count at diagnosis. A population pharmacokinetic model was used to estimate the correlations between baseline WBC count, volume of distribution and clearance of DNR. RESULTSA clear but weak inverse relationship between the baseline WBC count and plasma concentrations of DNR (r 2 = 0.11, P < 0.05) at time 1 was found. Furthermore, a clear relationship between baseline WBC count and DNR central volume of distribution using population pharmacokinetic modelling (dOFV 4.77, P < 0.05) was also noted. Analysis of plasma DNR and the metabolite daunorubicinol (DOL) concentrations in patients with a high WBC count support that the low DNR/DOL concentrations are due a distribution effect. CONCLUSIONThis study shows that the leukaemic cell burden influences the plasma concentrations of anthracyclines. Further studies are needed to explore if patients with high a WBC count may require higher doses of anthracyclines.

Population pharmacokinetics of cytarabine, etoposide, and daunorubicin in the treatment for acute myeloid leukemia

“…In a previous study, it was shown that the baseline white blood cell count (bWBC) was inversely correlated with the plasma concentration of Dnr [11]. Interestingly, a similar effect has been described for Ara-C in a constant infusion regimen [12], whereas other investigators did not find this correlation for patients receiving higher doses of Ara-C (1,000-3,000 mg/m 2 ) [13].…”

“…The reduction in OFV indicated that there was also support for this relationship in the current data. For comparison, the differences in parameter estimates and uncertainties, along with the parameter estimates from the prior study [11], can be seen in Table 3. The Vc was increased by 1.9% for each increase in bWBC of 1 9 10 6 cells/mL.…”

“…The residuals and weighted residuals will not be calculated with the M3 method for individuals who have both continuous dependent variables and a likelihood, i.e., those with a BLQ observation. The relatively sparse data in this study for Dnr analysis combined with the availability of information from a previous PK analysis with Dnr [11] led to the investigation of the PRIOR function in the Dnr model development. This method, in which the prior parameter estimates and their uncertainty are considered, may stabilize parameter estimation with the new data by imposing a penalty function on the OFV.…”

“…Models for the three drugs were developed with the software NONMEM Ò , including data for observations below the limit of quantification with the M3 method [17] and for daunorubicin with the inclusion of information from a similar prior PK study with the subroutine PRIOR [11,18].…”

Rewired Metabolism in Drug-resistant Leukemia Cells

“…1B). This is a clinically relevant drug resistance level as DNR dosing during induction regimens is in the range of 60 -80 mg/m 2 for adult (Ͼ15 years) ALL patients (23), corresponding to plasma DNR concentrations of ϳ0.2-1.4 M after a 1-h infusion (24). The generation and characteristics of the HL60/R10 cells are described in Ref.…”